MicroRNAs (miRNAs) have emerged as a promising new class of therapeutics for cancer. miRNAs are small, non-coding RNAs that determine cell fate by post-transcriptionally regulating the expression of a broad but nevertheless specific set of genes. miRNAs can function as conventional oncogenes and tumor suppressors and, when misregulated by e.g. aberrant expression, miRNAs can contribute to the development of cancer. We hypothesize that countering this misregulation - either by miRNA replacement with miRNA mimics or by miRNA inhibition with miRNA antagonists - will interfere with the cancerous phenotype and induce a therapeutic response. Among the most well-known tumor suppressor miRNAs to date is miR-34, the lead candidate for therapeutic development of Mirna Therapeutics. Mirna Therapeutics has generated extensive data describing the anti-tumor activity of miR-34 in mouse models of human primary and metastatic prostate cancer. However, a clinically-relevant delivery technology is required to bring a miR-34 therapeutic to the clinic. Our proposal explores chemically modified chitosan nanoparticles as a delivery vehicle that would facilitate the systemic administration of miRNAs to orthotopically grown prostate tumors. In collaboration with Dr. Roy at the University of Texas in Austin, we will develop functionalized chitosan nanoparticles that show enhanced properties for miRNA delivery and low toxicity. We will determine biodistribution and half-life of these nanoparticles in plasma and various tissues test for delivery to orthotopic prostate tumors and most importantly, inhibition of primary and metastatic tumor growth. We believe these studies will help developing a delivery technology that enables the systemic administration of therapeutic miRNAs to prostate tumors and potentially other solid tumors and will advance the development of therapeutic miRNAs closer to the clinic. PUBLIC HEALTH RELEVANCE: Advanced prostate cancer continues to be the second leading cause of cancer deaths in males, and is often resistant to conventional therapeutics. Our work may lead to the development of microRNA-based therapies that can be systemically administered and are highly and specifically active towards prostate cancer cells. This will result in a reduced incidence of death from prostate cancer.